Hereditary cerebellar ataxias represent a heterogeneous group of neurodegenerative disorders characterized by loss of control of body movements. Degeneration of Purkinje cells in the cerebellum is one of the most common neuropathological features of these diseases. Even if intensive scientific research in the last years led to the identification of several disease mechanisms, an effective treatment for cerebellar ataxias is still lacking.

The main focus of my research is the dissection of the molecular pathogenesis of two inherited forms of cerebellar ataxia, namely Spinocerebellar ataxia type 28 (SCA28) and autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS), which peculiarly have in common alterations of mitochondrial dynamics as the main cause of Purkinje cell degeneration. Indeed, mitochondria are dynamic organelles which continuosly change their shape in response to cellular needs and are also actively recruited to dendrites and axons. The identification of a common mitochondrial way to Purkinje cell degeneration will be instrumental to develop target therapy for both diseases.

Curriculum Vitae

Education

2008: PhD in Molecular Medicine, University Vita-Salute San Raffaele, Milan.

2003: Master’s degree in Pharmaceutical Biotechnologies (magna cum laude), University of Milan.

Professional Experiences

2014-present: Researcher in Medical Genetics (MED/03), Università Vita-Salute San Raffaele.

2008-2013: Postdoc, Neurogenomics Unit, San Raffaele Scientific Institute, G. Casari’s lab.

2007-2008: Visiting scientist, Aarhus University Hospital Skejby, Denmark, P. Bross lab.

2004-2008: PhD student in Molecular Medicine (section of Neuroscience), University Vita-Salute San Raffaele, G.Casari’s lab.

2003-2004: Fellow, University of Milano-Bicocca, M.L. Lavitrano’s lab.

2002-2003: Undergraduate student, San Raffaele Scientific Institute, A. Servadio’s lab.

Grants

2016-2018: Research Grant from Ataxia Charlevoix-Saguenay Foundation, Montreal Québec, Canada.

2014-2017: Giovani Ricercatori, bando 2011-2012 from the Italian Ministery of Health.

2012-2014: Young Investigator Award for the SCAs Research, from National Ataxia Foundation, Minneapolis (USA).

Teaching appointments

2016-present: Lecturer at the School of Medicine, Università Vita-Salute San Raffaele, Master Degree in Medicine and Surgery, Course of Genetics and Developmental Biology.

2015-present: Lecturer at the School of Medicine, Università Vita-Salute San Raffaele, Bachelor Degree in Medical and Pharmaceutical Biotechnology, Course of Genetics and Molecular Biology.

2013-present: Tutor at the School of Medicine, Università Vita-Salute San Raffaele, International MD Program, Course of Genetics and Developmental Biology.

2011-present: Lecturer at the School of Medicine, University Vita-Salute San Raffaele, Bachelor Degree in Nursing, Coordinator of the Course “Fondamenti Biomolecolari della vita”.

Research Activity

The role of mitochondrial dynamics and motility in cerebellar degeneration

Hereditary cerebellar ataxias are a group of genetic disorders characterized by progressive incoordination of gait, often associated with poor coordination of hands, speech, and eye movements. Ataxia results from degeneration of neurons in the cerebellar cortex, brain stem, spinocerebellar tracts and their afferent/efferent connections. Degeneration of Purkinje cells in the cerebellum is one of the most common neuropathological features of these diseases.

Purkinje cells are neurons with unique features: they are characterized by a large soma and extensive dendritic trees, receiving glutamate excitatory synaptic input and therefore being exposed to high Ca2+ concentrations. Synapses of Purkinje cell dendrites need a more precise control of Ca2+ homeostasis compared to other neurons, implying higher levels of ATP and higher Ca2+ buffering power. These features suggest that proper mitochondrial functionality and distribution to microdomains of large ion fluxes represent crucial issues in Purkinje cells. In fact, mitochondria not only provide ATP to active Ca2+ clearance systems at the plasma membrane, but also exert themselves a fine shaping of Ca2+ signals by accumulating Ca2+ into the matrix. Mitochondria are extremely dynamic organelles, modulating their morphology through fusion and fission processes that create highly interconnected tubular networks as well as solitary organelles. Moreover, mitochondria are actively transported to subcellular sites, such as the axonal and dendritic processes of neurons.

The project aims at dissecting the molecular pathogenesis of two inherited forms of cerebellar ataxia, SCA28 and ARSACS, which peculiarly have in common alterations of mitochondrial dynamics as the main cause of Purkinje cell degeneration. The main objectives are: (i) to define the molecular mechanisms leading to altered mitochondrial dynamics when the disease-gene is mutated; (ii) to investigate how perturbation of mitochondrial dynamics impact on mitochondrial trafficking and lead to Purkinje cell degeneration. To this end, we will apply integrated approaches of mouse and cell biology, molecular biology and neurobiology, which rely on already available in vivo and in vitro models and patient samples. The identification of common pathogenetic pathways will be instrumental to develop target therapy for both diseases.

Publications

  1. ADuncan EJ, Larivière R, Bradshaw TY, Longo F, Sgarioto N, Hayes MJ, Romano LEL, Nethisinghe S, Giunti P, Bruntraeger MB, Durham HD, Brais B, Maltecca F, Gentil BJ, Chapple JP. Altered organisation of the intermediate filament cytoskeleton and relocalisation of proteostasis modulators in cells lacking the ataxia protein sacsin.Hum Mol Genet. 2017 May 23.
  2. Maltecca F, Baseggio E, Consolato F, Mazza D, Podini P, Young SM Jr, Drago I, Bahr BA, Puliti A, Codazzi F, Quattrini A, Casari G. Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model. J Clin Invest. 2015 Jan;125(1):263-74.
  3. Magnoni R, Palmfeldt J, Christensen JH, Sand M, Maltecca F, Corydon TJ, West M, Casari G, Bross P. Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in mice. Neurobiol Dis. 2013 Jun;54:12-23.
  4. Maltecca F, De Stefani D, Cassina L, Consolato F, Wasilewski M, Scorrano L, Rizzuto R, Casari G. Respiratory dysfunction by AFG3L2 deficiency causes decreased mitochondrial calcium uptake via organellar network fragmentation. Hum Mol Genet. 2012 Sep 1;21(17):3858-70.
  5. Maltecca F, Magnoni R, Cerri F, Cox GA, Quattrini A, Casari G. Haploinsufficiency of AFG3L2, the gene responsible for spinocerebellar ataxiatype 28, causes mitochondria-mediated Purkinje cell dark degeneration. J Neurosci. 2009 Jul 22;29(29):9244-54.
  6. Maltecca F, Aghaie A, Schroeder DG, Cassina L, Taylor BA, Phillips SJ, Malaguti M, Previtali S, Guénet JL, Quattrini A, Cox GA, Casari G. The mitochondrial protease AFG3L2 is essential for axonal development. J Neurosci. 2008 Mar 12;28(11):2827-36Maltecca F, Filla A, Castaldo I, Coppola G, Fragassi NA, Bruni A, Cocozza S, Casari G, Servadio A & De Michele G. Intergenerational instability and marked anticipation in SCA17. Neurology 2003; 61(10):1441-3.